This proposal is structured to provide some answers to questions about the nature of the molecular interactions between adrenergic agents and their sites of action: 1. What are the stereochemical requirements for approach and binding of an agonist to its site of action? 2. What binding forces are involved between the agonist and its site of action? 3. How can theoretical molecular orbital calculations help in (a) analysis and interpretation of the above interactions, and (b) providing predictions about the adrenergic receptors and other sites of action that can be confirmed or refuted by direct experimental observations? These questions will be attacked by: 1. synthesis of a series of rigid analogs of adrenergic amines with a varied, but fixed, stereochemical relationship between the functional groups known to be necessary for adrenergic activity. 2. determination of the relative pharmacological activity of each compound using both standard pharmacological tests with whole animals and organ systems as well as specific enzyme assay methods with COMT and monoamine oxidase, and calculation (computer molecular orbital calculations) of the lowest energy or preferred conformation of known adrenergic agents. 3. correlation of the calculated preferred conformation with the pharmacological activity of the synthetic compounds, and 4. interpretation of the results in terms of the stereochemical and binding requirements of the adrenergic receptor and their consistency with current hypothetical models of the adrenergic receptors and other sites of action.